Trimethyl orthoformate → 1-({4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2h-pyran-4-yl}methyl)-1h-imidazo[4,5-c]pyridine

HRID 273049Notes

Reaction equation

HRID 273049 reaction equation
[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[NH2:30])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[C:24]5[CH:29]=[CH:28][N:27]=[CH:26][C:25]=5[N:30]=[CH:31]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

4

Reactant 2

HCID 9005Trimethyl orthoformateHCID 131727198N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine

Product 1

HCID 598374831-({4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2h-pyran-4-yl}methyl)-1h-imidazo[4,5-c]pyridineYield 65%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Procedure

N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (280 mg, 0.68 mmol), trimethylorthoformate (5 mL) and formic acid (0.5 mL) were stirred at 40° C. for 18 hours then at 60° C. for 24 hours, then at 80° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between 2M NaOH (30 mL) and DCM (2×30 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound as a clear viscous oil (185 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 4H), 1.91-2.03 (m, 4H), 2.15-2.20 (m, 2H), 2.52 (m, 4H), 2.61 (t, 2H), 3.44 (m, 2H), 3.82 (m, 2H), 4.00 (t, 2H), 4.19 (s, 2H), 6.82 (d, 2H), 6.86-6.93 (m, 3H), 7.08 (s, 1H), 8.30 (d, 1H), 9.01 (s, 1H). HRMS ESI+ m/z 421.2590 [MH]+.

Workup

  1. waitat 80° C. for 24 hours
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. customthe residue partitioned between 2M NaOH (30 mL) and DCM (2×30 mL)
  4. dry with materialdried over sodium sulphate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give a brown oil
  8. customThe crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume)

Sources & evidence

ORD record
ord-148e65cdb8fe465f8a6e9c151a0d7bbe
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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